title: Effects of adjuvant chemoradiotherapy on the frequency and function of regulatory T cells in patients with head and neck cancer.
abstract: OBJECTIVE
  Regulatory T cells (Treg) accumulate in tumor tissues and the peripheral blood of cancer patients and may persist after therapies. This cross-sectional study examines effects of adjuvant chemoradiotherapy (CRT) on Treg numbers and function in head and neck squamous cell carcinoma (HNSCC) patients.
  
  
  METHODS
  The frequency and absolute numbers of CD4(+), ATP-hydrolyzing CD4(+)CD39(+) and CD8(+) T cells, and expression levels of CD39, CD25, TGF-β-associated LAP and GARP on Treg were measured by flow cytometry in 40 healthy donors (NC) and 71 HNSCC patients [29 untreated with active disease (AD); 22 treated with surgery; 20 treated with CRT]. All treated subjects had no evident disease (NED) at the time of phlebotomy. In an additional cohort of 40 subjects with AD (n = 15), NED (n = 10), and NC (n = 15), in vitro sensitivity of CD4(+) T-cell subsets to cisplatin and activation-induced cell death (AICD) was tested in Annexin V-binding assays.
  
  
  RESULTS
  CRT decreased the frequency of circulating CD4(+) T cells (P < 0.002) but increased that of CD4(+)CD39(+) Treg (P ≤ 0.001) compared with untreated or surgery-only patients. Treg frequency remained elevated for >3 years. CRT increased surface expression of LAP, GARP, and CD39 on Treg. In vitro Treg were resistant to AICD or cisplatin but conventional CD4(+) T cells (Tconv) were not. CRT-induced Treg from AD or NC subjects upregulated prosurvival proteins whereas Tconv upregulated proapoptotic Bax.
  
  
  CONCLUSIONS
  Highly suppressive, cisplatin-resistant Treg increase in frequency and persist after CRT and could be responsible for suppression of antitumor immune responses and recurrence in HNSCC.
authors.affiliation: Authors' Affiliations: University of Pittsburgh Cancer Institute; University of Pittsburgh School of Medicine; Departments of Pathology, Immunology, and Otolaryngology, Pittsburgh, Pennsylvania; Department of Otolaryngology, University of Essen, Germany; and Department of Surgery, Fukushima Medical University, Fukushima, Japan.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Schuler
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Harasymczuk
authors.forename: Bastian
authors.initials: B
authors.lastname: Schilling
authors.forename: Zenichiro
authors.initials: Z
authors.lastname: Saze
authors.forename: Laura
authors.initials: L
authors.lastname: Strauss
authors.forename: Stephan
authors.initials: S
authors.lastname: Lang
authors.forename: Jonas T
authors.initials: JT
authors.lastname: Johnson
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000628:therapy; D016022:Case-Control Studies; D059186:Chemoradiotherapy, Adjuvant; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000628:therapy; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000517:prevention & control*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin